Highly lipophilic camptothecin derivatives (HLCDs), particularly those containing silicon-based moieties, are effective anticancer drugs. One of the most noted of the silicon-containing HLCDs has the IUPAC name (4S)-4-ethyl-4-hydroxy-11-[2-(trimethylsilyl)ethyl]-1H-pyrano[3′:4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione, and has also referred to as 7-(2′-trimethylsilyl)ethyl camptothecin (also known as Karenitecin™ and BNP1350), currently in human clinical trials in the United States and internationally. U.S. Pat. No. 5,910,491 and others describe the compositions, formulations, and processes for making Karenitecin™ and other related HLCDs.
Currently known most preferred processes for making Karenitecin™ are described and claimed in U.S. Pat. No. 6,194,579 (the '579 patent), incorporated herein by reference, and in U.S. patent application Ser. No. 10/627,444, filed Jul. 25, 2003. In the '579 patent, Karenitecin™ and other silicon-containing HLCDs are manufactured by reacting camptothecin with a TMS-aldehyde and a strong oxidizing agent (hydrogen peroxide is preferred) in the presence of a metal sulfate to effect a Minisci-type alkylation. As described in the '579 patent, the resulting alkylation moiety contained one less carbon atom than the TMS-aldehyde, a typical characteristic of the Minisci alkylation.
The prior patented process for synthesizing Karenitecin was efficient in small-scale (laboratory-scale) production, but improvements were necessary to enable efficient larger scale production. Improvements were needed primarily to boost yields by optimizing process parameters and reagents of choice (and accordingly reduce impurities) and also in analytical methods to address the impurity profile of the active pharmaceutical ingredient (powder form BNP1350), and to simplify the purification process to make it user friendly and robust for manufacturing scale. The prior process resulted in a 50%–60% crude theoretical yield and a 25% to 35% isolated yield after column chromatography. The new process, disclosed herein, demonstrated approximately an 80% crude theoretical yield and a 45% to 50% isolated yield after double crystallization.
Other prior processes for synthesizing HLCDs can be found in U.S. Pat. No. 6,150,343 and others. These prior processes utilize a total synthesis route to synthesize the camptothecin skeleton. Due to the relatively low yields and higher costs of these methods when compared to semisynthetic methods, they are considered impractical and inefficient for conducting large-scale synthetic operations.
U.S. patent application Ser. No. 10/627,444, filed Jul. 25, 2003, referred to above describes and claims a modified process for synthesizing HLCDs. In the modified process disclosed in the '444 patent application, the main difference in the process was the addition of a nonpolar, aprotic solvent to the initial mixture of the trimethylsilyl aldehyde reactant in order to boost yields.